Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A defect in the skeletal muscle sarcoplasmic reticulum (SR) calcium release channel of malignant hyperthermia-susceptible (MHS) pigs greatly enhances SR calcium release in pigs homozygous for the malignant hyperthermia (MH) gene. In pigs heterozygous at this locus, rates of calcium release from isolated SR stimulated by Ca2+, ATP, or caffeine are intermediate to those of both MHS and normal SR [Mickelson et al. Am. J. Physiol. 257 (Cell Physiol. 26): C787-C794, 1989]. In this study bundles of intact muscle cells dissected from pigs of various genotypes were used to examine the effects of the MH gene on contractile responses to caffeine (direct stimulation of the SR) or to surface membrane (sarcolemma) depolarization (i.e., stimulation by way of the steps in excitation-contraction coupling). The caffeine threshold for contractures in the heterozygous muscles (5 mM) was intermediate to both types of homozygous muscles (2 mM for MHS and 10 mM for normal) as is the case with direct stimulation of calcium release from SR vesicles [Mickelson et al. Am. J. Physiol. 257 (Cell Physiol. 26): C787-C794, 1989]. Sarcolemmal depolarization was elicited by electrical stimuli or elevated extracellular potassium. Control twitch tension for MHS and heterozygous muscles did not differ and was significantly greater in both than in homozygous normal muscles. Potassium-induced contractures were significantly larger in MHS and heterozygous than in normal muscles. Thus, in heterozygous muscles, force production via sarcolemmal depolarization (twitches and potassium contractures) was enhanced as much as in homozygous MHS muscles. This could be the result of feedback from abnormal SR calcium channels producing altered (enhanced) transverse tubule to SR signal transduction.
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PMID:Excitation-contraction coupling in pigs heterozygous for malignant hyperthermia. 153 30

1. Azumolene sodium is a new water-soluble derivative of dantrolene sodium that also acts as a skeletal-muscle relaxant. 2. Azumolene (6 mumol/L) inhibited the hypercontractility induced separately by 3% halothane, 2 mmol/L caffeine and 80 mmol/L potassium chloride in isolated malignant hyperpyrexia (MH)-susceptible muscle. Azumolene was equipotent with dantrolene in inhibiting the abnormal responses. 3. Like dantrolene, azumolene (6 mumol/L) not only prevented but reversed the abnormal contractures induced by halothane and caffeine. Contracture responses to caffeine were also modified by azumolene in control preparations. 4. In the presence of maximal effective concentrations of dantrolene, azumolene failed to further relax caffeine-induced contractures, and the converse was also true. This was observed in both MH-susceptible and control preparations. 5. Sarcoplasmic reticulum Ca(2+)-dependent ATPase activity from MH-susceptible and control muscle was not affected by azumolene. 6. Like dantrolene, azumolene may inhibit Ca2+ release directly from the sarcoplasmic reticulum and be of therapeutic value for the treatment of MH.
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PMID:The effect of azumolene on hypercontractility and sarcoplasmic reticulum Ca(2+)-dependent ATPase activity of malignant hyperpyrexia-susceptible porcine skeletal muscle. 183 2

This report describes a cardiac arrest that occurred in a 4-month-old infant during induction of anesthesia. During the administration of N2O/O2 and halothane via a face mask tachycardia was noted and rigor followed the application of succinylcholine for intubation. Shortly thereafter cardiac arrest occurred; 15 min later we found a profound metabolic acidosis as well as signs of rhabdomyolysis with a serum potassium level of 10.3 mmol/l and an increase in serum creatine kinase (CK). While performing cardiopulmonary resuscitation (CPR) and treating the acid-base imbalance and hyperkalemia, we administered--suspecting malignant hyperthermia (MH)--dantrolene. Approximately 60 min post-arrest we achieved stabilization of the vital signs. During the following hours the CK level rose to 99, 600 IU/l and myoglobinuria of 360,000 micrograms/l confirmed the extent of the rhabdomyolysis. The infant was discharged home without detectable sequelae after 2 1/2 weeks. Comparisons with corresponding case reports in the literature lead to the supposition that our patient suffered from a myopathy thus far undiagnosed. To what extent a MH episode may have contributed to the clinical picture cannot be determined at present. The spectrum of adverse reactions to volatile anesthetics and succinylcholine in patients with myopathic disorders is presented and discussed. As in other case reports, the dramatic course described here also demonstrates that in addition to CPR and treatment of the acid-base and electrolyte imbalances, administration of dantrolene should be considered at an early stage.
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PMID:[Cardiac arrest during anesthesia induction with halothane and succinylcholine in an infant. Massive hyperkalemia and rhabdomyolysis in suspected myopathy and/or malignant hyperthermia]. 195 45

In pigs, the serotonin-2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 0.8 mg/kg, induced "psychotic" behaviour (e.g., grimacing, backward locomotion, blank stare) and a muscular syndrome, which is known as malignant hyperthermia (MH) in pigs and humans. This syndrome is characterized by generalized skeletal muscle rigidity, leading to an increase in body temperature, marked acidosis, hyperkaliaemia, cyanosis and elevation of lactate, carbon dioxide and the muscle enzyme creatine kinase (CK) in plasma. In pigs which were selectively bred for susceptibility to MH induction by known triggering agents, such as halothane, the administration of DOI was fatal in 3 out of 5 animals. In genetically susceptible pigs, MH was also induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 0.5-1.8 mg/kg, and D-lysergic acid diethylamide (LSD), 60-110 micrograms/kg. Furthermore, 5-MeO-DMT and LSD induced head shakes in the animals, which had not been observed after DOI and could not be blocked by 5-HT2-antagonists, ketanserin (0.5-5 mg/kg) and ritanserin (1-2.5 mg/kg). The psychotomimetic effects of 5-MeO-DMT could be blocked by ketanserin or ritanserin, which, depending on the dose, also reduced or totally prevented the hyperthermia and metabolic changes induced by 5-MeO-DMT in pigs. Administration of 5-MeO-DMT, 1.8 mg/kg, was fatal in 4 of 5 MH-susceptible pigs, whereas pigs injected with this dosage after pretreatment with ketanserin (0.5-5 mg/kg) or ritanserin (1-2.5 mg/kg) did not die. In pigs from MH-resistant littermates, administration of 5-MeO-DMT was not fatal. Comparison of metabolic changes in susceptible and non-susceptible pigs suggested that the marked increase in plasma potassium, which arises principally from damaged muscle cells, is primarily responsible for the fatal effect of DOI and 5-MeO-DMT in genetically susceptible individuals. In MH-susceptible pigs, which were anesthetized, relaxed and artificially ventilated, 5-MeO-DMT did not induce hyperthermia, thus substantiating that the marked hyperthermia observed in conscious pigs was a result of muscle activation and not due to effects on thermoregulation or blood pressure. The results indicate that hallucinogenic drugs with 5-HT2 agonistic effects trigger a life-threatening syndrome, MH, in genetically susceptible pigs. 5-HT2 antagonists, such as ketanserin or ritanserin, are capable of counteracting the fatality of this syndrome.
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PMID:Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia. 211 35

Signs of malignant hyperthermia, including progressive increases in PaCO2, skin temperature and heart rate, and elevated serum levels of potassium, inorganic phosphate, and creatine kinase, were identified in a halothane-anesthetized horse. Treatment was discontinuing halothane administration, applying ice and cold fluids, and hyperventilating with 100% oxygen. After an initial recovery, bilateral hindlimb myopathy and pigmenturia developed. The myopathy resolved after treatment with oral dantrolene, IV fluids, and hydrocortisone. Results of caffeine-halothane challenge, using semimembranosus muscle collected 2 weeks after the episode, were considered within normal limits for horses. The intraoperative abnormalities were evidently predictive of postanesthetic myopathy but the cause in this horse remained unclear.
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PMID:Postanesthetic equine myopathy suggestive of malignant hyperthermia. A case report. 260 79

We report on a patient with neuroleptic malignant syndrome (NMS) caused by a therapy for endogenous depression. The symptoms were hyperpyrexia (39.2 degrees C), rigidity, elevated creatine kinase (CK: 594 U/l) and coma. After transfer from an outside hospital, he was treated, at first without effect with dantrolene p.o. (80 mg q.i.d.) and i.v. (1 mg/kg-1/h-1). Clinical improvement and temperature reduction were noted when the levels of neuroleptic drugs fell during unspecific intensive care with mechanical ventilation, sedation (flunitrazepam, barbiturates), relaxation (pancuronium), and hydration. After uncomplicated weaning from the ventilator the patient became more cooperative and was returned to the psychiatric ward. Further treatment took the form of combined drug therapy with biperiden and flunitrazepam and in addition a series of 12 electroconvulsive therapies (ECT). The elevated CK levels initially decreased, serum potassium levels were found to be within normal limits, and myoglobinuria was not detected during the further course. Trigger agents for NMS are antipsychotic drugs such as thioxanthenes, phenothiazines and butyrophenones. Because the signs and symptoms are so similar to those of malignant hyperthermia (MH), it has been suggested that NMS and MH are related diseases. The postulated mechanisms of NMS become apparent in the CNS, whereas those of MH affect the muscle cell itself. An abnormal in vitro contraction test after NMS should suggest to triggering of MH crisis after succinylcholine administration in anaesthesia for ECT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The malignant neuroleptic syndrome and malignant hyperthermia]. 272 40

Diltiazem inhibited and antagonized the abnormal contractures induced by halothane, caffeine and potassium chloride in isolated skeletal muscle from pigs susceptible to malignant hyperpyrexia (MHS). Contractile responses to caffeine and electrical stimulation also were suppressed by diltiazem in control tissue. Similar effects were obtained in the presence of dantrolene. In both MHS and control preparations, diltiazem antagonized caffeine-induced contractures in the presence of maximal effective concentrations of dantrolene, and the converse was true also. In MHS and control preparations detubulated by glycerol, diltiazem did not inhibit or antagonize caffeine-induced contractures while dantrolene did. Diltiazem seems to modify contractile responses at the level of the transverse tubule membrane by inhibiting the inward flow of extracellular Ca2+, while dantrolene inhibits Ca2+ release directly from the sarcoplasmic reticulum. Ca2+ influx through transverse tubules may be important in the aetiology of the MH syndrome.
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PMID:Effect of diltiazem and dantrolene on the contractility of isolated malignant hyperpyrexia-susceptible porcine skeletal muscle. 273 Aug 30

The effects on whole body or cardiac metabolism of carbon dioxide, calcium, potassium, or digoxin were studied in 16 normal swine and 31 swine susceptible to malignant hyperthermia (MHS). Malignant hyperthermia (MH) was defined as an increase in metabolism that occurred in MHS but not in normal pigs. Whole body response: despite a sustained PaCO2 greater than 130 mmHg, MH did not develop in four intact MHS swine during thiopental-N2O anesthesia and controlled ventilation. Drugs given during total cardiopulmonary bypass: MH did not develop in five MHS pigs with blood ionized calcium to 15 mEq/l, in four MHS pigs with digoxin levels to 60 ng/ml, or in four normal pigs with potassium to 10 mEq/l. In six MHS pigs, oxygen consumption increased from 6.5 to 11.6 ml O2 X min-1 X kg-1 when potassium exceeded 6 mEq/l; lactate did not increase. Cardiac response (during extracorporeal right heart bypass): eight pigs (four normal, four MHS) with blood ionized calcium to 5 mEq/l and eight pigs (four normal, four MHS) with digoxin levels above 7.5 ng/ml had increased myocardial oxygen consumption. Cardiac potassium efflux or lactate production did not occur in normal or MHS pigs. Increased arterial potassium (7.4-8.5 mEq/l) did not alter myocardial oxygen consumption or lactate production in four MHS or four normal pigs. MH responses were initiated only by potassium and only in regard to whole body metabolism. Cardiac metabolism increased as a result of specific drugs (calcium, digoxin), unrelated to MH phenomena. Porcine inbreeding resulting in MH susceptibility of skeletal muscle does not imply abnormality in other tissues.
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PMID:Effect of CO2, calcium, digoxin, and potassium on cardiac and skeletal muscle metabolism in malignant hyperthermia susceptible swine. 307 72

The concurrent administration of dantrolene and verapamil has the theoretical advantage of being more efficacious than dantrolene alone in the treatment of malignant hyperthermia. However, the combination has been reported to cause fatal hyperkalemia in pigs. The present study evaluated the serum concentrations of cations, serum osmolarity, and cardiovascular responses in 20 mongrel dogs after dantrolene with and without the concurrent administration of verapamil. The dogs were randomly classified into four groups of five dogs each: group 1 received neither dantrolene nor verapamil; group 2 received three successive intravenous doses of dantrolene (1, 3, and 6 mg/kg) at 30-minute intervals; group 3 received verapamil 0.1 mg/kg IV bolus, followed by a continuous infusion of 5 micrograms.kg-1.hr-1; and group 4 received verapamil as in group 3, followed by dantrolene as in group 2. Measurements were made at 15-minute intervals for 2 1/2 hours. Progressive and similar statistically significant increases in mean serum potassium occurred after 105 minutes in dogs given dantrolene (group 2, mean peak serum potassium levels 5.4 +/- 0.5 mmol/L) and after 90 minutes in dogs given verapamil-dantrolene (group 4, 5.2 +/- 1.6 mmol/L). A statistically significant decrease in serum sodium levels was also found in groups 2 and 4. One dog in group 4 developed intermittent second-degree heart block after the final dose of dantrolene. Serum calcium levels (ionized and total) tended to decrease in groups 2 and 4. There were no statistically significant differences in osmolarities, cardiac outputs, or mean arterial blood pressures among groups. In summary, significant elevations of serum potassium were observed in this dog model given dantrolene with and without verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperkalemia after dantrolene and verapamil-dantrolene administration in dogs. 339 63

A healthy, 15-year-old male received a thiopental, nitrous oxide, oxygen, enflurane anesthetic for appendectomy. Cardiac arrest, following succinylcholine administration, was associated with marked hyperkalemia (potassium levels 8.7 to 11.6 meq), hemolysis (hematocrit fall from 41.7 to 26.6%, plasma hemoglobin 27 mg/dL), and creatine phosphokinase (CPK) elevation (8900 units). Vigorous resuscitative therapy including dantrolene was unsuccessful. The diagnosis of malignant hyperthermia was made by the marked CPK elevation on blood samples drawn during resuscitation and analyzed by the Medical Examiner's Office.
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PMID:Hemolysis and hyperkalemia complicate malignant hyperpyrexia during anesthetic death. 371 29


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